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Hum Mol Genet. 2010 Oct 1;19(19):3693-701. doi: 10.1093/hmg/ddq284. Epub 2010 Jul 20.

Deducing the pathogenic contribution of recessive ABCA4 alleles in an outbred population.

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Howard Hughes Medical Institute, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA 52242, USA.


Accurate prediction of the pathogenic effects of specific genotypes is important for the design and execution of clinical trials as well as for meaningful counseling of individual patients. However, for many autosomal recessive diseases, it can be difficult to deduce the relative pathogenic contribution of individual alleles because relatively few affected individuals share the same two disease-causing variations. In this study, we used multiple regression analysis to estimate the pathogenicity of specific alleles of ABCA4 in patients with retinal phenotypes ranging from Stargardt disease to retinitis pigmentosa. This analysis revealed quantitative allelic effects on two aspects of the visual phenotype, visual acuity (P < 10(-3)) and visual field (P < 10(-7)). Discordance between visual acuity and visual field in individual patients suggests the existence of at least two non-ABCA4 modifying factors. The findings of this study will facilitate the discovery of factors that modify ABCA4 disease and will also aid in the optimal selection of subjects for clinical trials of new therapies.

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